The present invention, in some embodiments thereof, relates to therapy and more particularly, but not exclusively, to compounds, compositions and methods useful in inhibiting a kinase, in modulating a biological activity of a chemokine, in inhibiting cancel cells, in inhibiting chemokine-dependent cell migration and/or in treating diseases and disorders associated with kinase activity, biological activities of chemokines and/or cell migration, such as cancer and inflammatory diseases and disorders.
Chemokines are among the many biological factors that are involved in the inflammatory disease process. Chemokines belong to a group of small, about 8-14 kDa, mostly basic, heparin-binding proteins that are related both in their primary structure and the presence of 4 conserved cysteine residues.
The chemokines are chemotactic cytokines that have been shown to be selective chemoattractants for leukocyte sub-populations in vitro, and to elicit the accumulation of inflammatory cells in vivo. In addition to chemotaxis, chemokines mediate leukocyte de-granulation [B aggiolini and Dahinden, Immunol Today 1994, 15:127-133], up-regulation of adhesion receptors [Vaddi and Newton, J Immunol 1994, 153:4721-4732], and suppression of human immunodeficiency virus replication [Cocchi et al., Science 1995, 270:1811-1815].
Chemokines play an essential role in the recruitment and activation of cells from the immune system. They also have a wide range of effects in many different cell types beyond the immune system, including for example, in various cells of the central nervous system [Ma et al., PNAS 1998, 95:9448-9453], and in endothelial cells, where they result in either angiogenic or angiostatic effects [Strieter et al., J Biol Chem 1995, 270:27348-27357]. Particular chemokines may have multiple effects on tumors, including angiogenesis, promotion of growth and metastasis, and suppression of the immune response to cancer, while other chemokines inhibit tumor-mediated angiogenesis and promote anti-tumor immune responses.
Chemokine receptors have received increasing attention due to their critical role in the progression of inflammation and associated conditions such as asthma, atherosclerosis, graft rejection, AIDS and autoimmune conditions (e.g., multiple sclerosis, arthritis, myasthenia gravis, lupus).
SDF-1 (stromal cell-derived factor 1), also known as CXCL12 (C-X-C motif chemokine 12), is a chemokine which is strongly chemotactic for lymphocytes. SDF-1 plays an important role in angiogenesis, including angiogenesis associated with tumor progression, by recruiting endothelial progenitor cells from the bone marrow, an effect mediated by the CXCR4, the receptor for SDF-1 [Zheng et al., Cardiovasc Pharmacol 2007, 50:274-280; Kryczek et al., Am J Physiol Cell Physiol 2007, 292:C987-C995]. In addition, cancer cells that express CXCR4 are attracted to metastasis target tissues that release SDF-1.
Plerixafor, an antagonist of CXCR4, is used in combination with G-CSF (granulocyte colony-stimulating factor) to mobilize hematopoietic stem cells in cancer patients, particularly lymphoma and multiple myeloma patients. The stem cells are subsequently transplanted back to the patient after chemotherapy or radiotherapy.
In animal studies, plerixafor has also been reported to reduce metastasis Smith et al., Cancer Res 2004, 64:8604-8612], to reduce recurrence of glioblastoma associated with vasculogenesis [Kioi et al., J Clin Investigation 2010, 120:694-705], and to counteract opioid-induced hyperalgesia [Wilson et al., Brain Behav Immun 2011, 25:565-573].
Kinases are a family of enzymes that mediate the transfer of a phosphate moiety from a high energy molecule (such as ATP) to a substrate. Kinases are involved in many cell-signaling pathways. Protein kinases act on proteins, phosphorylating serine, threonine, tyrosine, or histidine residues in the protein, and thereby affecting the protein's activity.
Mitogen activated protein kinases (MAPK) constitute a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The p38 MAPKs (p38α, p38β, p38γ and p38δ), for example, are responsible for phosphorylating and activating transcription factors (such as ATF-2, MAX, CHOP and C/ERPb) as well as other kinases (such as MAPKAP-K2/3 or MK2/3), and are themselves activated by physical and chemical stress (e.g. UV, osmotic stress), pro-inflammatory cytokines and bacterial lipopolysaccharide (LPS) [Stein et al., Ann Rep Med Chem 1996, 31:289-298; Herlaar & Brown, Molecular Medicine Today 1999, 5:439-447]. The products of p38 phosphorylation have been shown to mediate the production of pro-inflammatory cytokines.
The implication of kinases pathways on various diseases and disorders, and an anti-inflammatory activity of kinase inhibitors have been described in the art. For example, anti-inflammatory activities have been reported for p38 kinase inhibitors [Badger et al., J Pharm Exp Thera 1996, 279:1453-1461; Griswold et al., Pharmacol Comm 1996, 7:323-229]. In particular, p38 kinase inhibitors have been described as potential agents for treating rheumatoid arthritis, and to exhibit beneficial effects in models of airway diseases such as COPD and asthma [Haddad et al, Br J Pharmacol 2001, 132:1715-1724; Underwood et al., Am J Physiol Lung Cell Mol 2000, 279:895-902; Duan et al., Am J Respir Crit Care Med 2005, 171:571-578; Escott et al., Br J Pharmacol 2000, 131:173-176; Underwood et al., J Pharmacol Exp Ther 2000, 293:281-288]. The implication of the p38MAPK pathway in various diseases has been reviewed by Chopra et al. [Expert Opinion on Investigational Drugs 2008, 17:1411-1425].
The compound 8-(2,4-dihydroxy-6-(2-oxoheptyl)-phenoxy)-6-hydroxy-3-pentyl-1H-isochromen-1-one was isolated from oakmoss, and reported to exhibit potent antibacterial activity against Legionella, but not against other bacteria [Nomura et al., Biol Pharm Bull 2012, 35:1560-1567].
Arjunolic acid [Ramesh et al., Nat Prod Res 2012, 26:1549-1552], auraptene [Epifano et al., Phytother Res 2013, 27:784-786; Genovese & Epifano, Curr Drug Targets 2011, 1:381-386] and falcarindiol [Huang et al., Molecules 2014, 19:6142-6162; Wang et al., Phytomedicine 2013, 20:999-1006] have been reported to inhibit cancer cells. Auraptene has also been reported to suppress MCP-1 expression in adipocytes [Kuroyanagi et al., Biochem Biophys Res Commun 2008, 366:219-215].